Although much work has been accomplished in developing improved models for the structure of membranes and lipoproteins, there is relatively little known about the thermodynamics of lipid-protein association in real or suitable model systems. We propose to show that the thermodynamic models based upon the interior of a lipid bilayer or monolayer as a hydrocarbon are incorrect because they do not adequately allow for the penetration of water into the phospholipid hydrocarbon region. As a result, the hydrophobic gradient between water and the phospholipid interior is much smaller than that existing between pure hydrocarbon and water. Furthermore, the magnitude of the free energy of transfer, DeltaGt, of a protein from water to a membrane or lipoprotein usually calculated from the sum of the DeltaGt's of the individual amino acid side chains is too large since they are based upon partitioning of amino acids between water and air or an organic phase. We propose to measure the hydrophobic gradient between water and the middle of a lipid bilayer by monitoring the wavelength maxima and quenchability of indole labeled fatty acids. We will measure the equilibrium constant, Kb, for the binding of real and model apolipoproteins to bilayer membranes and lipoproteins in direct binding assays based upon intrinsic tryptophan fluorescence, sedimentation or chromatography. Comparison of the DeltaGt based on Kb for the apolipoproteins should enable one to predict which ones bind best to phospholipids. We believe that our measurements and the proof of our hypotheses will provide investigators in the area of membrane and lioprotein dynamics with a better quantitative basis for understanding how proteins associate with lipids. This information is particularly important in those systems in which an cofactor apolipoprotein is bound to a lipid-protein complex which is the substrate for a lipid-catabolizing enzyme. Catabolism of the lipid changes the macromolecular structure and the DeltaGt. As a consequence the apoprotein will be transferred to a new particle where it repeats its activation on another ensemble of lipids.